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The Role of SAHA in Attenuating Liver Fibrosis

Al Saad, Sarah (2022) The Role of SAHA in Attenuating Liver Fibrosis. Master's Thesis, University of Pittsburgh. (Unpublished)

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Chronic liver disease (CLD) is one of the leading causes of morbidity and mortality globally. There are approximately 1.5 billion cases of CLD worldwide, with 4.5 million cases in the United States alone. Most types of CLD are a result of a wound healing process that leads to extracellular matrix deposition and scar tissue formation, or liver fibrosis. When left untreated, liver fibrosis may progress to cirrhosis or hepatocellular carcinoma, and ultimately liver failure, thereby requiring liver transplantation. Unfortunately, the only treatment available for liver fibrosis is removal of the causative agent. This highlights the importance of finding novel therapeutic targets and repurposing drugs to treat liver fibrosis. Histone deacetylase inhibitors (HDACi) have been reported to be beneficial in diseases of fibrosis. Vorinostat, or suberoylanilide hydroxamic acid (SAHA), a pan HDACi used to treat T-cell lymphoma, was reported to inhibit hepatic stellate cell activation and liver fibrosis. However, the mechanism behind this attenuation has yet to be explored in detail. We previously published that overexpression of a redox regulator, Glutaredoxin-1 (Glrx) is protective in liver fibrosis. Therefore, I investigated whether SAHA inhibits hepatic stellate cell activation by upregulating Glrx. I first confirmed SAHA’s inhibition of both human and mouse hepatic stellate cell activation and attenuation of liver fibrosis in a carbon tetrachloride mouse model. SAHA also significantly upregulated the expression of Glrx in both mouse and human hepatic stellate cells. Knockdown of GLRX partially attenuated SAHA’s inhibitory effect on HSC activation. Based on these results, I conclude that SAHA’s inhibition of hepatic stellate cell activation may be Glrx-dependent.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Al Saad, Sarahska32@pitt.eduska32
ContributionContributors NameEmailPitt UsernameORCID
Committee ChairXie, Wenwex6@pitt.eduwex6UNSPECIFIED
Committee MemberMa, XiaochaoMXIAOCHA@pitt.eduMXIAOCHAUNSPECIFIED
Committee MemberYang, Dadyang@pitt.edudyangUNSPECIFIED
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXie, Wenwex6@pitt.eduwex6
Committee MemberMa, XiaochaoMXIAOCHA@pitt.eduMXIAOCHA
Committee MemberYANG, Dadyang@pitt.edudyang
Date: 7 April 2022
Date Type: Submission
Defense Date: 5 April 2022
Approval Date: 8 April 2022
Submission Date: 8 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 40
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: No
Uncontrolled Keywords: SAHA, Glutaredoxin-1, hepatic stellate cells, liver fibrosis
Date Deposited: 08 Apr 2022 18:46
Last Modified: 08 Apr 2022 18:46


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